Schistosomes and other snail-transmitted parasites persist as significant public health problems, particularly in children and women, across much of the developing world. The use by these parasites of freshwater snails as intermediate hosts makes control very difficult. We need to develop a broader base of knowledge regarding these parasites, particularly in light of recent concerns about the potential evolution among schistosomes of resistance to praziquantel. This proposal focuses on the interactions between two trematodes, Schistosoma mansoni and Echinostoma paraensei, and their molluscan host Biomphalaria glabrata, with the goal of obtaining a deeper understanding of how these parasites establish infections in snails, and more importantly, how the snail can overcome these infections. Capitalizing on discoveries made during our previous funding period, we intend to further characterize the structure, diversity and genomic organization of members of a family of B. glabrata blood proteins termed fibrinogen-related proteins or FREPs, that have several attributes that make them likely candidates as non-self recognition molecules in B. glabrata. As such, they may be key regulators of the molluscan response to trematode infection and become particularly useful in future attempts to develop transgenic snails resistant to schistosome infection. Because FREPs exist in a multigene family and are invertebrate members of the immunoglobulin superfamily, they also provide a unique model to study the evolution of invertebrate immune responses. Also outlined are experiments to characterize the molecules used by trematode larvae in affecting host defense cells (hemocytes) and to identify hemocyte molecules that are targeted for attack. Finally, we propose to examine a model system in which snails can be provoked to develop acquired resistance to trematode infection. We will apply the tools and insights developed in recent years to this model to reveal the factors most closely linked to the resistant state. These studies will provide novel insights pertaining to both basic and applied aspects of schistosome (trematode) biology.